SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity

Interthal, Heidrun; Chen, Hong Jing; Kehl-Fie, Thomas E.; Zotzmann, Jörg; Leppard, John B.; Champoux, James J.

doi:10.1038/sj.emboj.7600694

Cited by 185 publications

(231 citation statements)

References 46 publications

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“…3C) [40]. The second S N 2 reaction step in the Tdp1 catalytic mechanism is supported by in vitro biochemical studies with the SCAN1 H493R mutant, which leads to an accumulation of Tdp1-DNA covalent intermediate [28]. Overall, the final product released after Tdp1 catalysis is a DNA molecule with a 3′-phosphate end (Fig.…”

Section: Biological Functions and Catalytic Mechanismmentioning

confidence: 68%

“…Specifically, homozygous mutant SCAN1 cells have been shown to accumulate more total DNA strand breaks than normal lymphoblastoid cells after treatment with CPT [24,72]. SCAN1 cells have also demonstrated enhanced sensitivity to the killing effects of CPT [28,72]. Furthermore, complementary studies have shown that overexpression of wild-type Tdp1 protects cells against CPT-induced cell death [26,73], whereas the inactive mutant Tdp1 H263A does not [26].…”

Section: Rationale For Targeting Tdp1 For Cancer Therapymentioning

confidence: 84%

“…Initially, it was proposed that the SCAN1 mutation disrupted the Tdp1 active site symmetry leading to a loss-of-function [21,24,27], yet recent studies have suggested an additional hypothesis wherein the accumulation of covalent Tdp1-DNA intermediates might be responsible for the DNA damage leading to the SCAN1 phenotype (see Fig. 3, legend) [28].…”

Section: Biological Functions and Catalytic Mechanismmentioning

confidence: 99%

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Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

144

203

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolates and 3′-abasic sites indicating it may function as a general 3′-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

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Section: Biological Functions and Catalytic Mechanismmentioning

confidence: 68%

Section: Rationale For Targeting Tdp1 For Cancer Therapymentioning

confidence: 84%

Section: Biological Functions and Catalytic Mechanismmentioning

confidence: 99%

See 1 more Smart Citation

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

144

203

View full text Add to dashboard Cite

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“…CPT-induced cell death was also observed in yeast and human tdp1 mutants. The human Tdp1 gene in SCAN1 cells is hypersensitive to CPT and induces cell death in treated cells (El-Khamisy et al, 2005;Interthal et al, 2005). Yeast tdp1 mutants, when coupled with mutation of the other DNA repair genes, show a significant effect on the survival of CPT-treated cells Liu et al, 2002Liu et al, , 2004Vance and Wilson, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…As in yeast, the human Tdp1 protein plays a role in the repair of topoisomerase I-DNA complex lesions in SCAN1 cells (El-Khamisy et al, 2005;Miao et al, 2006). SCAN1 cells are hypersensitive to CPT (Interthal et al, 2005;Miao et al, 2006) and accumulate single-strand break and double-strand break DNAs by CPT (El-Khamisy et al, 2005).…”

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confidence: 99%

Identification of Tyrosyl-DNA Phosphodiesterase as a Novel DNA Damage Repair Enzyme in Arabidopsis

et al. 2010

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a key enzyme that hydrolyzes the phosphodiester bond between tyrosine of topoisomerase and 3#-phosphate of DNA and repairs topoisomerase-mediated DNA damage during chromosome metabolism. However, functional Tdp1 has only been described in yeast and human to date. In human, mutations of the Tdp1 gene are involved in the disease spinocerebellar ataxia with axonal neuropathy. In plants, we have identified the functional nuclear protein AtTDP, homolog to human Tdp1 from Arabidopsis (Arabidopsis thaliana). The recombinant AtTDP protein certainly hydrolyzes the 3#-phosphotyrosyl DNA substrates related to repairing in vivo topoisomerase I-DNA-induced damage. The loss-of-function AtTDP mutation displays developmental defects and dwarf phenotype in Arabidopsis. This phenotype is substantially caused by decreased cell numbers without any change of individual cell sizes. The tdp plants exhibit hypersensitivities to camptothecin, a potent topoisomerase I inhibitor, and show rigorous cell death in cotyledons and rosette leaves, suggesting the failure of DNA damage repair in tdp mutants. These results indicate that AtTDP plays a clear role in the repair of topoisomerase I-DNA complexes in Arabidopsis.

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The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl‐DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

Keil

Frese-Schaper

Steiner

et al. 2015

Arthritis & Rheumatology

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Objective. The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan.Methods. NZB/NZW mice were treated with lowdose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of antidouble-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay.Results. Compared to treatment with either agent alone, simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/ NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti-dsDNA antibodies. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding.Conclusion. Affecting DNA relaxation by the enzymes topo I and TDP-1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.Systemic lupus erythematosus (SLE) is a chronic autoimmune disease mainly affecting women of childbearing age. It is estimated that in the US up to 275,000 adult women have SLE (1). The disease involves different organs, but immune complex glomerulonephritis most strikingly influences the course of SLE. Between 10% and 30% of patients with lupus nephritis develop end-stage renal disease (ESRD) resulting in the requirement for hemodialysis or kidney transplantation (2). Due to the application of immunosuppressive drugs, the survival of patients with lupus-associated glomerulonephritis increased from a 5-year rate of 44% in the 1950s to a 10-year rate of 88% recently (3). Despite these advances in the treatment of SLE, the life expectancy of patients with lupus and renal damage was recently demonstrated to be 23.7 years shorter than that in the general population (4). Moreover, the incidence of ESRD associated with lupus nephritis did not decrease over recent years (5), indicating that current medication is insufficient to treat lupus nephritis.Treatment with nonselective immunosuppressive drugs continues to be the central strategy for controlling lupus nephritis. Treatment consists of induction therapy with cyclophosphamide and prednisolone or mycophenolate mofetil follow...

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SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity

Cited by 185 publications

References 46 publications

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Identification of Tyrosyl-DNA Phosphodiesterase as a Novel DNA Damage Repair Enzyme in Arabidopsis

The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl‐DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

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